Natural bone is a biocomposite of collagen, non-collagenous organic phases including glycosaminoglycans, and calcium phosphate. Its complex hierarchical structure leads to exceptional mechanical properties including high stiffness, strength, and fracture toughness, which in turn enable bones to withstand the physiological stresses to which they are subjected on a daily basis. The challenge faced by researchers in the field is to make a synthetic material that has a composition and structure that will allow natural bone growth in and around the synthetic material in the human or animal body.
It has been observed that bone will bond directly to calcium phosphates in the human body (a property referred to as bioactivity) through a bone-like apatite layer formed in the body environment. Collagen and copolymers comprising collagen and other bioorganics such as glycosaminoglycans on the other hand, are known to be optimal substrates for the attachment and proliferation of numerous cell types, including those responsible for the production and maintenance of bone in the human body.
Hydroxyapatite is the calcium phosphate most commonly used as a constituent in bone substitute materials. It is, however, a relatively insoluble material when compared to other forms of calcium phosphate materials such as brushite, tricalcium phosphate and octacalcium phosphate. The relatively low solubility of apatite can be a disadvantage when producing a biomaterial as the rate of resorption of the material in the body is particularly slow.
Calcium phosphates such as hydroxyapatite are mechanically stiff materials. However, they are relatively brittle when compared to natural bone. Collagen is a mechanically tough material, but has relatively low stiffness when compared to natural bone. Materials comprising copolymers of collagen and glycosaminoglycans are both tougher and stiffer than collagen alone, but still have relatively low stiffness when compared to natural bone.
Previous attempts to produce a synthetic bone-substitute material having improved mechanical toughness over hydroxyapatite and improved stiffness over collagen and copolymers of collagen and glycosaminoglycans include combining collagen and apatite by mechanical mixing. Such a mechanical method is described in EP-A-0164 484.
Later developments include producing a bone-replacement material comprising hydroxyapatite, collagen and chondroitin-4-sulphate by the mechanical mixing of these components. This is described in EP-A-0214070. This document further describes dehydrothermic crosslinking of the chondroitin-4-sulphate to the collagen. Materials comprising apatite, collagen and chondroitin-4-sulphate have been found to have good biocompatibility. The mechanical mixing of the apatite with the collagen, and optionally chondroitin-4-sulphate, essentially forms collagen chondroitin-4-sulphate-coated particles of apatite. It has been found that such a material, although biocompatible, produces limited in-growth of natural bone when in the human or animal body and no remodeling of the calcium phosphate phase of the synthetic material.
Previous work has developed means through which the parameters of freeze-drying protocols can be controlled to produce porous scaffolds of collagen and one or more glycosaminoglycans (GAGs). These techniques allow scaffold features such as pore size and aspect ratio to be varied in a controlled manner, parameters known to have marked effects on the healing response at sites of trauma or injury. However, for treatment of injuries involving skeletal and musculoskeletal defects, it is necessary to develop technologies to produce porous scaffolds with material compositions and mechanical characteristics that closely match those of bone, as opposed to those of unmineralised collagen-GAG scaffolds.
The applicant's earlier International patent application, PCT/GB2006/000797, filed 6 Mar. 2006, relates to materials for biomedical applications and, in particular, to porous monolithic and porous layered scaffolds comprising, for example, collagen, calcium phosphate, and optionally a glycosaminoglycan. The content of PCT/GB2006/000797 is also set out in the Annex attached hereto so as to aid a better understanding of the present invention.